Transgenerational epigenetic inheritance: from phenomena ... · the molecular basis of epigenetic inheritance has become the goal of a growing ﬁeld of research. Identifying the

Transgenerational epigenetic inheritance:from phenomena to molecular mechanismsNoa Liberman1,2,3, Simon Yuan Wang1,2,3 andEric Lieberman Greer1,2

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Inherited information not encoded in the DNA sequence can

regulate a variety of complex phenotypes. However, how this

epigenetic information escapes the typical epigenetic erasure

that occurs upon fertilization and how it regulates behavior is

still unclear. Here we review recent examples of brain related

transgenerational epigenetic inheritance and delineate

potential molecular mechanisms that could regulate how non-

genetic information could be transmitted.

Addresses1Division of Newborn Medicine, Boston Children’s Hospital,

300 Longwood Avenue, Boston, MA 02115, USA2Department of Pediatrics, Harvard Medical School, Boston MA 02115,

USA

Corresponding author:

Greer, Eric Lieberman ([email protected])3Co-first authors.

Current Opinion in Neurobiology 2019, 59:189–206

This review comes from a themed issue on Neural epigenetics

Edited by Michael Greenberg and Stavros Lomvardas

https://doi.org/10.1016/j.conb.2019.09.012

0959-4388/ã 2019 Elsevier Ltd. All rights reserved.

IntroductionSince the discovery that genomic DNA transmitted heri-

table information 75 years ago [1�], the vast majority of

traits have been found to follow Mendelian inheritance.

However, since Alexander Brink first reported transge-

nerational epigenetic inheritance in maize in 1956, the

number of examples of non-Mendelian inheritance con-

tinues to grow [2�]. Non-genetic information has been

shown to regulate an increasing number of complex

phenotypes, including physical appearance [3�,4], energy

metabolism [5], behavioral state [6�], and longevity [7–9].

Misregulation of epigenetic inheritance causes imprint-

ing disorders in humans [10], and non-genetic information

has also been implicated in inherited responses to envi-

ronmental change [11��,12]. For example, human epide-

miological data suggest that poor diet of parents and even

grandparents increases susceptibility to obesity [13].

Extending beyond the phenomenology to understand

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the molecular basis of epigenetic inheritance has become

the goal of a growing field of research. Identifying the

mechanistic basis by which epigenetic information from a

parent can be transmitted across generations in model

organisms could define basic mechanisms of transgenera-

tional inheritance relevant to human health. In this

review, we highlight some recent examples of transge-

nerational epigenetic inheritance induced by behavioral

and environmental manipulations, focusing on brain

related phenotypes, and discuss the potential molecular

mechanisms that could underlie the transmission of non-

genetic information between generations.

Behavioral and environmental changes thatalter inheritanceNon-Mendelian inheritance, termed transgenerational

epigenetic inheritance, has been reported in a wide range

of both prokaryotes and eukaryotes. These phenomena

may have evolved to allow organisms to adapt to extreme

environmental conditions and transmit information criti-

cal for survival under adverse conditions to their progeny

without mutating the genome. By avoiding mutation,

stressed organisms may be able to return to a basal state

once conditions improve. Stimuli shown to trigger trans-

generational inheritance may be environmental, such as

changes in temperature [14–17], oxygen availability [18],

amount of sunlight [19], osmotic stress [20], odorants

[6�,21], radiation [22], and diet [23�,24,25�,26]; or behav-

ioral, such as predation [27], exercise [28�], and trauma

[29–32]. These factors are thought to signal through the

somatic tissues of the body to the germline, or directly to

the germline, to alter the epigenome and induce effects in

subsequent generations (Figure 1). As these phenomena

are just beginning to be described, the critical steps

involved in sensing, signaling, and epigenetic alterations

and maintenance are still largely unknown.

In what follows we describe some examples of pheno-

types in multiple species that have been attributed to

epigenetic inheritance and review the evidence.

Traumatic stress

In humans and other species, traumatic experiences in

the parental generation have been shown to alter the

biological phenotypes of offspring, even in the absence of

the initial stressor. Predators induce the crustacean Daph-nia magna to mature more rapidly and increase reproduc-

tion, changes that persist for two additional generations


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190 Neural epigenetics

Figure 1

Predation Parental care Microbiota

Osmotic stressExerciseOdorHypoxia

StressDiet

RadiationTemperatureSolar radiation

DNA methylationHistone modificationNon-coding RNAsPrion

Soma

Germline

P0

F1

Fn

-O2

?

Current Opinion in Neurobiology

Several behavioral and environmental cues have been proposed to induce phenotypic changes in the parental generation that can be transmitted

to subsequent generations through the germline in a non-genetic manner.

even in the absence of predators. However, how this

epigenetic state is induced or inherited is still unclear

[27]. Correlative studies suggest that stress induces heri-

table consequences in humans. The offspring of stressed

fathers are more susceptible to stress themselves [31].

Similarly, male and female offspring of stressed adult

mice display depression and anxiety behaviors that cor-

relate with altered plasma corticosterone and gene

expression [32]. The children of parents who experienced

post-traumatic stress disorder (PTSD) or were Holocaust

survivors had elevated cortisol and DNA methylation

alterations. In particular the chaperone gene FKBP5has decreased DNA cytosine methylation in the children

of Holocaust survivors [29]. Cortisol was reduced in

mothers and their babies who were diagnosed with PTSD

in response to September 11 [30]. It is still unclear

whether these epigenetic differences in progeny are

reactions to a still stressed parent or transmission of

stress-induced epigenetic changes from stressed parent

to offspring.


Parental care

Maternal behavior can also shape the development of

offspring in subsequent generations. Several studies have

suggested that the offspring of mothers who do not

provide appropriate care in the postpartum period are

also deficient in nurturing their newborns. Women who

grew up in institutional settings without parental care

behave less sensitively and more aggressively towards

their own children [33]. Female rats frequently lick and

groom their offspring during the first week postpartum

[34]. Offspring reared by mothers who do not do this have

elevated stress hormone levels and hypothalamic-pitui-

tary-adrenal activity [35�] and are less likely to lick and

groom their own offspring [36]. Another rodent model of

impaired maternal care used mice heterozygous for a

mutation of Peg3, which show increased neophobia and

decreased exploratory behavior. Peg3 is an imprinted gene

expressed exclusively from the paternal allele [37]. When

Peg3 heterozygous females are crossed with wildtype

males, the wild-type daughters and granddaughters do


Mechanisms of transgenerational epigenetic inheritance Liberman, Wang and Greer 191

not retrieve their pups normally, even though the grand-

daughters were raised by wild-type mothers. These

results have been interpreted as examples of non-genetic

inheritance of maternal behavior. An alternate explana-

tion could be that early memories of maternal behavior

cause alterations in the newborn brain that affect later

behavior in the adult animal that can be passed on to

future generations. Yet, there are some indications that

epigenetic changes may be at work. A high frequency of

pup licking and grooming in mice has been correlated

with decreased DNA cytosine methylation of the ERal-pha1b promoter in female offspring [38]. However,

whether DNA methylation regulates maternal grooming

and is transgenerationally transmitted has not been exam-

ined. Chronic and unpredictable maternal separation in

the early life of newborn mice (postnatal day 1–14) can

trigger depression in mature animals [31,39]. The F1, F2

and F3 generations of these maternally deprived animals

have decreased exploratory behavior, independently of

their genotype that persists even with cross-fostering.

This behavioral phenotype correlates with DNA cytosine

hypermethylation in MeCP2 and hypomethylation in

CRFR2 in the germline of F1 and F2 males. All of these

studies taken together suggest that deficient maternal

care of neonatal animals causes lasting psychological

damage in multiple subsequent generations. However,

whether this is due to transgenerational epigenetic inher-

itance or the consequences of learned behavior is not

clear.

Exercise

Environmental enrichment (EE) by a combination of

physical exercise and cognitive training of mice has been

shown to lead to elevated hippocampal synaptic plasticity

and enhanced learning and memory in the F1 offspring.

This enhanced learning was correlated with increased

miR-212/132 expression in the sperm and hippocampus

of the mice [28�]. Sperm RNA from EE or control fathers

was injected into fertilized oocytes and the progenies’

long term potentiation (LTP) and cognition were exam-

ined. Excitingly, mice from EE father sperm displayed

elevated LTP and a modest cognitive advantage. The

elevated LTP was reverted by treatment with miR212/

132 inhibitors but the cognitive advantage was not

affected. Together these results suggest the tantalizing

possibility that EE can induce heritable effects that are

partially regulated by sperm RNA. More experiments will

be needed to tease out what molecules are regulating the

heritable cognitive advantage of EE.

Olfaction

Odorants have also been proposed to induce epigenetic

changes in the offspring. The benzaldehyde and citro-

nellol odorants are attractants for Caenorhabditis elegansand contact with them leads to increased reproduction by

parents exposed during the larval L1 stage. Increased

fecundity was transmitted to unexposed F1, but not F2,


generation worms [21]. Surprisingly, repeated genera-

tional priming, over five successive generations, with

odorant exposure as larvae, led to a stronger chemotaxis

to these odorants than naıve descendants that persisted

for at least 40 generations [21]. How this non-genetic cue

is transmitted and whether these descendants would ever

revert to the ancestral naıve state or have undergone a

permanent genetic change remains to be determined.

Similarly, when parental mice are exposed to acetophe-

none in conjunction with fear conditioning, their naıve

unexposed F1 and F2 generation descendants show ele-

vated fear learning. A hint at a possible link to epigenetic

transmission is the observation that both conditioned

parents and naıve F1 generation mice have hypomethy-

lated cytosines at the olfactory gene Olfr151 [6�]. More

experiments are required to validate whether odorants

can induce transgenerational epigenetic inheritance and

to delineate the molecular mechanisms by which these

cues could be inherited.

These examples provide intriguing hints that transge-

nerational epigenetic inheritance could be a broadly

conserved phenomena regulating many different brain

related processes. However, it is clear that more experi-

ments must be performed to distinguish between learned

behaviors and bona fide epigenetic inheritance.

Molecular mechanismsDefinitive evidence for epigenetic inheritance and trans-

mission of complex phenotypes will require a molecular

understanding of the epigenetic changes that underlie

these phenotypes and how they are transmitted and main-

tained for multiple generations. In principle, any molecular

change in the zygote other than alterations in DNA

sequence could carry non-genetic information. These

include chemical modifications of DNA and chromatin

proteins and possibly modifications of non-coding RNA,

non-chromatin proteins or microbiota [40–42] (Figure 2).

Here we briefly describe examples of each of these modes

of non-genetic inheritance in diverse species. Comprehen-

sive reviews of what is known about epigenetic mecha-

nismsresponsiblefor inheritanceof transcriptionalmemory

are available [13,43–45].

DNA methylation

Because of the semi-conservative nature of DNA repli-

cation, DNA modifications can be inherited through cell

division [52,62�] and therefore provide an ideal carrier of

non-genetic information across generations. In eukar-

yotes, DNA methylation of the five carbon position of

cytosine (5mC) [46], which is catalyzed by the Dnmt

enzymes [47], is the predominant form of DNA modifi-

cation. 5mC is a stable but dynamic [52–54] transcrip-

tionally repressive epigenetic mark that regulates

development [55,56], differentiation [57,58], aging [59]

and disease [60,61]. The factors that mediate the initial

deposition, maintenance, and removal of DNA



Figure 2

Histones

DNA methylation

RNARNA

Prions

microbiota

Current Opinion in Neurobiology

Putative carriers of non-genetic information. Different mechanisms that may transmit non-genetic information are depicted here; DNA methylation,

non-coding RNAs, histone post translational modifications, prions and microbiota.

methylation are well characterized. Unmodified DNA can

be de-novo methylated by the DNA methyltransferase

enzymes, Dnmt3a and Dnmt3b [63,64] and established

methylation patterns can be maintained during DNA

replication by Dnmt1 [47,65,66]. Recruitment of these

methylases to DNA is mediated by additional factors such

as DNMT3L (de-novo) [67,68] and UHRF1 (mainte-

nance) [69,70]. DNA methylation can be removed

actively by Ten–eleven translocation (TET) family

demethylases, TET1, TET2 and TET3 [71–73], or

passively by successive rounds of replication [74].

There are several notable examples of DNA methylation

patterns that can be inherited across generations, includ-

ing imprinting of gene promoters and mobile DNA ele-

ments (e.g. transposons). Although 5mC moieties are

globally removed during fertilization of the zygote and

in primordial germ cells (PGCs) [75], a small subset of

cytosines are resistant to post-fertilization demethylation

and exhibit a form of intergenerational inheritance,

termed imprinting. For each imprinted gene, persistently

methylated cytosines occur specifically in either the

maternal or paternal DNA. Errors in the establishment

or maintenance of imprinting in the parental germ line

can lead to imprinting diseases, such as Prader–Willi

syndrome and Angelman syndrome [76]. While it is still

unclear how imprinted cytosines escape demethylation,

identifying the mechanisms and molecules that facilitate

this process may provide insight into how non-genetic


information can be transmitted across generations. In

addition, some imprinting can be established by

H3K27me3 rather than DNA methylation [77�]. Another

persistent form of epigenetic inheritance regulated by

DNA methylation suppresses activation of retrotranspo-

sons, such as Intracisternal A particles (IAPs), in the

mouse genome [78�]. Like imprinted genes, IAPs are

mostly methylated and silenced in the germline and resist

the wave of DNA demethylation during fertilization

[79,80]. One of the best characterized examples of epige-

netic inheritance in mammals is the agouti viable yellow

(Avy) locus in mice that determines coat color. Avy harbors

an IAP sequence upstream of the agouti coding sequence.

Avy expression varies among littermates depending on the

DNA methylation state of the IAP in the locus. The

spectrum of agouti phenotypes in the offspring depends

on the mother’s coat color. Maternal dietary supplemen-

tation with methyl donors shifts the coat color of the pups,

suggesting a connection between germ line methylation

and epigenetic memory in the progeny [3�,81–83]. Other

examples of inheritance and transposon silencing involv-

ing DNA methylation have been studied in plants [45,84],

making this one of the most well studied mechanisms of

transmission of non-genetic information.

Accumulating correlative epidemiological evidence sug-

gests that environmental signals can be encoded in DNA

methylation patterns that are subsequently passed on

through generations. For example, prenatal exposure to



famine during the Dutch Hunger Winter was associated

with lower cytosine methylation on the imprinted insulin-

like growth factor 2 (IGF2) gene [85] and decreased

cytosine methylation in the FKBP5 (FK506 Binding

Protein 5) gene was correlated with stress levels in the

offspring of Holocaust survivors [29]. More direct evi-

dence of transgenerational inheritance of changes in 5mC

is provided by experimental manipulation in other organ-

isms. In mice, for example, nutritional deprivation in

utero reduces 5mC in sperm of adult progeny and leads

to metabolic perturbations [86�].

Because the molecular mechanisms for deposition and

maintenance of 5mC on DNA are understood, 5mC has

often been proposed as a mechanism underlying transge-

nerational inheritance. However direct molecular evi-

dence connecting environmental cues and stresses to

DNA methylation and its effect on progeny phenotypes

is scarce. Additional experimental evidence that 5mC is

responsible for transgenerational phenotypes is needed to

be certain that DNA methylation is an important carrier of

epigenetic information between generations. Interest-

ingly, rare DNA methylation events, such as methylation

on the six nitrogen position of adenine (6 mA), which is

frequent in prokaryotes, have been described in eukar-

yotes [48–50] and could also play a role in epigenetic

inheritance [49,51]. However, assaying this DNA mark

has been hampered by possible bacterial contamination of

eukaryotic samples and thus its contribution to epigenetic

inheritance remains to be determined once more sensi-

tive tools have been developed.

Proteins

Several proteins are transmitted from parents to children

in the zygote to facilitate early growth and cell divisions

[87–93]. One of the most well studied non-genetic pro-

teins which can be transmitted are the self-replicating

prions [94–96]. Prions are thought to have evolved to infer

beneficial phenotypes in response to adverse environ-

mental conditions [97–103] without permanently altering

the DNA sequence. However, prions were originally

characterized as the cause of several heritable neurode-

generative diseases including; Creutzfeldt–Jakob disease

(CJD), kuru, scrapie and bovine spongiform

encephalopathy, in humans, sheep and cows, respectively

[96,104–108]. Work in Saccharomyces cerevisiae [109–111],

has deciphered how altered proteins can self-perpetuate

in the absence of altered nucleic acids. The capacity of

prions to respond to environmental cues and subse-

quently be non-genetically transmitted is exemplified

by [URE3] and [PSI+]. In response to poor environmental

conditions, yeast will convert Ure2p to [URE3] and

Sup35 to [PSI+] [112�] which are cytoplasmically inher-

ited as non-mitochondrial, non-Mendelian dominant

traits [107,113–115]. Prions have the capacity to adopt

multiple conformations, at least one of which can self-

template over long biological timescales. Prion forming


proteins have a ‘native’ non-prion conformation, occa-

sionally these fold into a prion conformation that then

replicates itself by templating the conformational conver-

sion of other molecules of the same protein. These

changes in conformation alter the functions of the pro-

teins involved, resulting in phenotypes specific to each

determinant protein [99,110,116–125]. At the molecular

level, virtually all known prions produce new traits by

forming highly stable cross-beta-sheet amyloid fibers

[117,126–130]. Propagation of these traits, and the amy-

loids that confer them, relies on the severing of prion

templates into smaller ‘seeds’ by the protein-remodeling

factor Hsp104 [116,118,131]. These seeds are passed from

mother cells to their daughters, serving as ‘replicons’ to

template future rounds of assembly [116,118]. Thus,

inhibiting Hsp104 eliminates the prion state and its

heritable capacity [132–135]. It will be important, in

future studies, to determine whether these non-histone

proteins can carry non-genetic information in multicellu-

lar organisms.

Histone methylation

One specialized class of proteins which are poised to carry

non-genetic information across generations are histones.

Histones are the basic proteins that DNA is wrapped

around in order to package and organize chromatin into

the structural units termed nucleosomes [136,137].

Histone tails are heavily modified by a variety of post-

translational modifications (PTMs) including phosphor-

ylation, acetylation, ubiquitinylation, methylation,

ADP-ribosyation and sumoylation [138]. These reversible

modifications integrate environmental cues to contribute

to the control of gene expression by influencing chroma-

tin compaction and/or signaling to transcription factor

complexes [139]. To date, there are several potential

mechanisms by which histone PTMs can be maintained

through cell division and then across generations to mark

critical regions of the genome; nucleosomes can be

removed at the replication fork and immediately reap-

plied to alternating daughter strands [140,141��,142–146],the histones themselves can be replicated in a semi-

conservative manner [142,147], histones could be added

to specific newly synthesized DNA from a pool of pre-

modified histones, long ncRNA could be used to reapply

chromatin modifications in specific genomic locations

[148,149], RNAi machinery can play a role in maintaining

epigenetic memory [150–152], or histone modifying

enzymes are present at the replication fork and can

modify the newly incorporated histones [153�,154�]. Sev-

eral or all of these different modes of inheritance might

contribute to the epigenetic memory of histone modifica-

tions, and different combinations could be revealed in

different systems or in response to different initiating

signals. While the specific mechanism for the inheritance

of histone modifications is still being worked out, there is

already a rich literature out there demonstrating the

correlation between histone modifications and



transgenerational epigenetic inheritance which we will

briefly summarize here.

In several species, including yeast, C. elegans, D. melano-gaster, and plants, histone methylation, predominantly the

canonically repressive modifications H3K9me3 and

H3K27me3, has been shown to communicate with

and help to reinforce RNAi-mediated silencing across

generations [155,156]. Fission yeast have been used to

demonstrate that H3K9me-dependent heterochromatin

can be retained across generations in the absence of DNA

methylation [157]. In yeast, H3K9me-dependent hetero-

chromatin maintains silencing of centromeric RNAs and

transposons. siRNAs are produced from noncoding cen-

tromeric RNAs (ncRNAs) and loaded onto the RNA-

induced initiator of transcriptional silencing (RITS)

complex [158]. RITS is then directed to nascent noncod-

ing centromeric RNAs [159]. The RITS complex pro-

motes H3K9 methylation, spreading and maintenance by

recruiting the H3K9 methyltransferase Clr4/Suv39 [160].

Once this repressive state is set, the heterochromatic state

can be inherited in the absence of RNAi [157,161,162]. In

C. elegans exposure to high temperature leads to reduced

H3K9 modifications at a silenced transgene locus.

Genetic analysis indicates SET-25 as mediating this

effect [15]. MET-2-dependent H3K9 methylation sup-

presses transgenerational small RNA inheritance suggest-

ing that H3K9me3 might be required for specific

instances of siRNA-dependent inheritance [163]. The

H3K27 trimethyltransferase PRC2 is maternally supplied

to progeny and is required for active propagation of

H3K27me3 during early embryogenesis in several organ-

isms [164�]. Both H3K9 and H3K27 are affected by

paternal diet [165]. The sperm chromatin of both zebra-

fish and mammals contains the repressive mark

H3K27me3 and the active marks H3K4me2 and

H3K4me3, raising the possibility of inherited transmis-

sion of these marks [166]. Furthermore, it was shown in C.elegans that X chromosome inactivation can be interge-

nerationally transmitted from both oocytes and sperm to

the embryos [164�]. Fertility depends on continued X

chromosome repression in the germline, which requires

inheriting a repressed X chromosome. H3K27-methyl-

ated histones can transmit a short-term memory of

repression in embryos and maternally supplied PRC2

mediates through H3K27 histone methylation the long-

term memory of repression during development. In

worms lacking PRC2, a paternal repressed X chromosome

via H3K9 methylation provides an alternative mode of

transmitting X repression to progeny [164�].

There is also evidence for the inheritance of active

histone modifications. H3K4me1/2/3 generally, although

not always [42], characterize transcriptionally permissive

or active chromatin [167,168]. Mutations in proteins of

the Trithorax H3K4 trimethyltransferase complex,

WDR-5, ASH-2 and SET-2 cause a �20-30% extension


of C. elegans lifespan [169], which is transmitted for three

generations to genetically wildtype descendants [7].

Removal of the H3K4me3 demethylase RBR-2 abolished

the transmission of extended lifespan in WDR-5-

deficient worms, suggesting that this transgenerational

effect depends on histone methylation. Knock out of the

H3K4 methyltransferase set1, or complex subunit ash2 in

Dictyostelium eliminated the inheritance of active tran-

scriptional states [170], suggesting that H3K4me3 might

play a conserved role in regulating epigenetic memory.

Similarly, knockout of the H3K4me1/2 demethylase spr-5(the homologue of LSD1) in C. elegans, causes a transge-

nerationally progressive decline in fertility and a transge-

nerational extension of lifespan [171�,172] which can be

repressed by removal of an H3K4 methyltransfserase as

well as H3K9me3 regulating enzymes [172–174]. In

mammals, overexpression of human LSD1 in mouse

sperm resulted in deregulation of gene expression in

embryos and the effects were heritable across generations

[175]. H3K36me1/2/3 methylation is also generally asso-

ciated with actively expressed genes [176]. In C. elegans,embryos inherit H3K36me3-marked chromosomes from

both the oocyte and sperm and receive a maternal load of

MES-4 and MET-1 that are H3K36 methyltransferases.

In this model, MET-1 is suggested to mediate transcrip-

tion-coupled H3K36me3 in the parental germline while

MES-4 seems to transmit the H3K36me3 mark across

generations and through early embryo cell divisions by

maintaining inherited patterns of H3K36me3 [177].

RNA

A substantial quantity of non-coding RNA is both mater-

nally [178–182] and paternally [183–185] transmitted.

Non-coding RNAs play key roles in regulating gene

expression [179,186,187], genome stability [188–190],

development [191–193], differentiation [194–196] and

defense against foreign genetic elements [197–199].

Non-coding RNAs include long non-coding RNAs

>200nts and short non-coding RNAs <100nts. Short

non-coding RNAs are subdivided to additional classes;

miRNAs (micro RNAs), siRNAs (small-interfering

RNAs), piRNAs (PIWI-interacting RNAs), tRNAs (trans-

fer RNAs), tDRs or tsRNAs (tRNA-derived small RNAs)

and snoRNAs (small nucleolar RNAs) [200]). The best

characterized heritable RNAs are small interfering RNAs.

This system has been elegantly mapped out in yeast

[41,150,201], C. elegans [202–207], and D. melanogaster[189,208–210] and is reviewed elsewhere [211–214]. A

small subset of RNAi’s have been shown to be heritable,

although it is still unclear as to how these RNAi’s are

selected or transmitted. In C. elegans, RNAi’s are ampli-

fied by RNA-depedendent RNA polymerases [215–219]

which can be transmitted across generations

[197,205,220–222]. The heritable maintenance of silenc-

ing is dependent on the nuclear RNAi pathways

[205,206,215,221,223–227]. Hints of how RNAi’s can

selectively be transmitted across generations have been



proposed due to forward genetic screens which have

identified specific Argonauts [203,206,228–230] and a

conserved RNA helicase, ZNFX-1, that is involved with

formation of phase-separated granules bordering the

nucleus [230,231]. These germ granules could transmit

specific small RNAs across generations [232]. It is possi-

ble that RNAi’s are potentially marked and physically

separated into granules for transmission across genera-

tions. piRNAs have been identified in C. elegans[156,205,221], D. melanogaster [182,189,233,234], zebrafish

[190] and mammals [235–239] to maintain genome sta-

bility by silencing transposon elements. In C. elegans[156,205,221] and D. melanogaster [182,240,241] this func-

tion has been shown to be inherited across generations.

The transmission of dsRNA-initiated silencing between

cells requires the small RNA transporter and conserved

transmembrane protein SID-1 (systemic RNAi defec-

tive). SID-1 function in both the parent and progeny is

required for the efficient transmission of dsRNA-initiated

silencing from parent to progeny [242–247]. Interestingly,

the inheritance of small RNAs is restricted to 3–5 gen-

erations. Some exciting genetic work has begun to deci-

pher genes involved in this transgenerational timing [248]

and future work focusing on a deeper molecular charac-

terization of how this transgenerational clock is regulated

well help to illuminate how non-genetic information is

transmitted through small RNAs. In addition to the RNAi

machinery, work initially in yeast [223–226,249] and

subsequently in C. elegans [163,164�,205,227,250–253]has shown that histone methylation at H3K9 and

H3K27 can communicate to help reinforce the RNAi

maintenance machinery however H3K9 methylation

might not always play a role [254].

Exciting new research has linked C. elegans neuronal

activity and small RNAs to transgenerational inherited

behaviors. Exposure of C. elegans to a pathogenic bacteria

leads to an avoidance behavior which is transgeneration-

ally inherited for 4 generations. Small RNAs produced

from the bacteria cause an increase in expression of the

TGF-b ligand daf-7 in a set of specific neurons in mothers

and their descendants. This TGF-b ligand and the germ-

line piRNA machinery are required for the transgenera-

tional phenotype [255,256]. Another study recently

suggested that small RNAs produced in the neurons

can regulate chemotaxis via a germline specific argonaute

amplification of small RNAs for 3 generations [257].

These studies present exciting new paradigms and mech-

anistic insight into how environmental stimuli can signal

through RNA to regulate transgenerational behaviors. It

will be interesting in future studies to identify how

specific RNAs are selected to be transmitted and

how this epigenetic signal is stopped.

In mammals, less is known of the molecular mechanisms

that regulate RNA inheritance, however, several studies

have correlated heritable distinct RNA species which are


present in sperm and oocytes and can be carried into the

zygote upon fertilization. How these specific RNAs are

marked for generational retention is still unclear. Recent

work suggests that modifications to RNAs might be

involved in marking a subset of RNAs to regulate herita-

bility of metabolic phenotypes. The tRNA methyltrans-

ferase, DNMT2, partly through its enzymatic activity,

participates in transmission of paternally acquired meta-

bolic disorders in mice. Deletion of mouse, Dnmt2,

prevented the elevation of RNA modifications (m5C,

m2G) in sperm small RNA fractions that are induced

by a high-fat diet. Offspring produced from oocytes

injected with RNA from Dnmt2 KO sperm showed

reduced phenotypes associated with high-fat-diet-

induced metabolic disorders [258]. Intergenerational

transmission of small RNAs in mammals with effects

on progeny phenotypes involve miRNAs [185,259,260]

and tRFs [23�,184,258]. Interestingly, tRFs have mostly

been linked to the transmission of metabolic phenotypes

[23�,183,184,258,261–266].

In plants paramutation involves RNA-mediated heritable

chromatin changes and several genes in the RNAi path-

way have been implicated [267]. In paramutation, one

allele can stably alter the expression of a homologous

allele in trans. The first reported example of transgenera-

tional gene silencing by paramutation was in maize

[2�,268]. Individual alleles at three different color gene

loci gave rise to epialleles with reduced pigmentation.

These epialleles led to a heritable non-Mendelian silenc-

ing of the wildtype alleles in heterozygotes which can be

transmitted stably over many generations in the absence

of the original allele [269]. Together these examples

illustrate how ncRNA can transmit specific non-genetic

information across generations, and in certain instances

communicate with DNA and histone methylation to

reinforce and perpetuate non-genetic information.

Microbiota

In addition to heritable cues transmitted in the cell itself,

foreign microorgansisms in the form of microbiota —

which may include bacteria, viruses, and fungi — are

putative carriers of non-genetic information across gen-

erations. The vast majority of the human microbiota is

present in the gut which harbors an estimated 1013

microbes [270]. Early work in the 19th century from

Pasteur and Metchnikoff examined the microbiota-gut

interactions [271,272], however, advanced sequencing

technologies of the past decade have spurred a

renaissance of microbiota research and how these micro-

organisms respond to changing environment and are

transmitted within families and across generations

[273]. Host-microbe interactions have been studied in

a variety of model organisms, including H. vulgaris[274,275], C. elegans [276], E. scolopes [277,278], D. mela-nogaster [279,280], D. rerio [281], M. musculus [282] and H.sapiens [283], to regulate numerous pathological states,



mainly metabolic related to diseases such as inflammatory

bowel disease, colitis, obesity and diabetes [284] but also

neurological related disorders and depression [285–289].

In addition, the microbiota affects a wide spectrum of host

physiological traits, including development [290–292],

fitness behaviors [293–295], immunity [296,297], nutri-

tion [298,299], and longevity [300,301]. Mammalian

microbiota are acquired both vertically from mother to

offspring [302–305] and horizontally among non-relatives

through social interactions and shared environments

[305–308]. Several studies have reported the importance

of the fetal environment in the womb, and of postnatal

colonization of the gut by commensal bacteria [309–313].

The microbiota population of the infant that is influenced

by the maternal gut [309,314,315] is influenced by mode

of delivery [304] as well as breastfeeding [316–321].

Microbiota are also regulated by diet [322–326], and

are therefore well situated to transmit non-genetic cues

across generations. Once transmitted, microbiota commu-

nicate with host cells through ligands and receptors to

activate insulin signaling [290] and the TOR pathway

[291]. In addition, microbial produced metabolites also

seem to activate host cell signaling pathways [327–329]

and modulate enzymatic activities and pathways involved

in histone modifications [330–332] chromatin remodeling

[333] and DNA methylation [334–336] which can rein-

force non-genetic information. Many of these metabolites

such as folate, choline and butyrate are involved in one

carbon metabolism and the production of methyl donors

for cellular methylation reactions [288,337]. Other micro-

bial metabolites are donors of acetyl groups involved in

the formation of acetyl-CoA that participates in epige-

nomic acetylation reactions [338]. These metabolites and

signal molecules could therefore be transmitted from the

ancestral microbiota and lead to long-term indirect effects

via epigenetic mechanisms mentioned above. However,

evidence for the effect of microbiota on epigenetic mech-

anisms leading to heritable phenotypes is correlative and

therefore is a ripe field for future studies to probe mech-

anistically how microbiota could regulate transgenera-

tional epigenetic inheritance. Specifically, the evidence

that connects microbiota-gut interactions to this complex

relationship is still lacking. Some interesting results have

recently been demonstrated in the Drosophila microbiota-

gut system. Removal of commensal Acetobacter species

from F1 embryos did not alter F1 larvae development, but

caused F2 delay. Reintroduction of isolated Acetobacter

species prevented the inheritance of the delay and this

prevention was partly mediated by vitamin B2 (Ribofla-

vin) which is produced by these bacteria [339]. The

presence of gut bacteria affects gut transcriptome with

both upregulated and downregulated genes, the majority

of these are associated with immune responses, tissue

homeostasis, gut physiology, and metabolism [340]. Fur-

thermore, the involvement of microbiota in transgenera-

tional inheritance of environmental exposures was tested

by looking at transcriptional profiles of progeny of flies


reared in the cold versus normal temperatures. 116 genes

were found to be differentially regulated in a microbiome

dependent manner, 45 genes were upregulated,

expressed in various tissues and involved in cuticle

development, chitin metabolism and response to oxida-

tive stress. Most of the 71 genes that were downregulated

in response to the cold temperature were mainly highly

expressed in various parts of the fly’s gut and are involved

in cilium movement and multicellular organism repro-

duction [341]. In recent years there has been a growing

body of evidence supporting the pivotal role of the

microbiota population and diet on neurodevelopment

and behavior of the offspring [342–344]. The establish-

ment of the neonatal gut microbiota coincides with major

processes of neurodevelopment. Neurogenesis, the

development and maturation of the microglia, formation

of the blood-brain barrier and myelination are all influ-

enced by the presence of microbiota as shown in studies

utilizing germ free mice and perinatal administration of

antibiotics and probiotics. Furthermore, similar studies

have shown that the offspring exhibit hypoactivity, anxi-

ety-like behavior and reduced social behavior. These

studies are comprehensively reviewed elsewhere [342].

In addition, immune activation during fetus development

has potential implications on offspring physiology, neu-

ropathology and behavior, as well as the microbiome

[345,346]. The maternal microbiome and the microbiome

transmitted to the offspring, their metabolites, and other

microbial products seem therefore to be important in

driving healthy neurodevelopment, and when perturbed

are sufficient to induce behavioral deficits in offspring.

Each of these modes of epigenetic inheritance do not

function in isolation and, as we mention above, will

oftentimes communicate and reinforce other non-genetic

cues. Deciphering which specific molecules are transmit-

ted across generations to regulate complex traits remains

one of the outstanding questions of the field. Now that

epigenetic inheritance has been demonstrated to be so

pervasive, future studies focusing on the transmitted

molecules and the conservation of molecular mechanisms

will be essential.

The importance of rigorIt is clear that transgenerational epigenetic inheritance is

an exciting and dynamic field which illustrates the com-

munication between many layers of biological regulation.

However, it is also exceptionally prone to errors and

misinterpretations. Some prominent examples include

the extremes of Lamarckism, Lyshenckoism, and

Lamarckian eugenics [347]. In these instances, theories

rather than experiments were allowed to drive the scien-

tific progress. One prominent example stems from work

done in Ivan Pavlov’s lab, where a student had initially

demonstrated that mice became successively trained

across generations at responding to a bell to expect to

be fed. Upon further tests it was demonstrated that the



student had become a more efficient mice trainer rather

than the mice inheriting the memory of the bell from their

parents [348]. This example highlights the need for

rigorous controls within these experiments and the iden-

tification of the appropriate molecular mechanisms

through traditional necessity and sufficiency experi-

ments. As epigenetics is modulatory in its very nature,

resulting transgenerational phenotypes are often subtle

and therefore can be swayed by investigator bias. It is

therefore important to incorporate rigorous controls and

blind experiments to ensure that the results are robust.

Ultimately, the identification of the underlying molecular

mechanisms will facilitate more traditional necessity and

sufficiency experiments which will help to transition

transgenerational epigenetic inheritance more decisively

from phenomena to believable biology.

SummaryHere we have summarized some of the exciting recent

findings in the brain in the burgeoning field of Transge-

nerational Epigenetic Inheritance. We have laid out some

of the potential molecular mechanisms that could under-

lie how non-genetic information can be transmitted across

generations and discussed some of the controversies

inherent in studying traits which by their very nature

are modulatory and exist at the interface between genet-

ics and environment. It is becoming increasingly clear

that none of these epigenetic cues functions in isolation,

and that by their very nature epigenetic cues communi-

cate with each other to help reinforce epigenetic signa-

tures. The complex nature of transgenerational

epigenetic inheritance makes it a complex trait to tackle.

However, as the sequencing age has come into its own,

and the ease with which non-model organisms can be

adapted and manipulated, we will no longer be restricted

to studying canonical model organisms. Thus, this field

can expand to take advantage of the incredible diversity

throughout the eukaryotic kingdom to decipher how

these complex traits can be regulated.

Transgenerational Epigenetic Inheritance has been sub-

ject to many false starts. While the early extremes of

Lamarck and Lyshencko have not held up to the test of

time, it is becoming increasingly apparent that some non-

Mendellian Inheritance is contributing to our diversity.

Transgenerational Epigenetic Inheritance’s very nature

is susceptible to subtle changes in the environment and

therefore finding robust, reproducible paradigms of epi-

genetic inheritance is critical for pushing the field for-

ward. Now that we have entered the molecular age,

pushing beyond the correlative observations, where some

transgenerational phenomena are associated with epige-

netic changes towards direct manipulation of the epigen-

ome to test whether epigenetic manipulations are not

only necessary but also sufficient, independent of the

initiating stimuli, to regulate transgenerational epigenetic

phenotypes will be critical to push this field forward. The


recent advent of tools to direct epigenetic modifications

to specific loci, such as the fusion of a nuclease null Cas9

to chromatin modifying enzymes to target epigenetic

regulators to specific loci [349], will be critical for deter-

mining the sufficiency of epigenetic changes to regulating

transgenerational epigenetic inheritance phenotypes and

probing whether these tantalizing preliminary results will

stand the test of time.

Conflict of interest statementNothing declared.

AcknowledgementsWe thank E. Pollina and J. Lieberman for critically reading the manuscript.S.Y.W. was supported by a Croucher Foundation fellowship. This work wassupported by the National Institutes of Health (grant numbersR00AG043550, R21HG010066, and DP2AG055947).

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Transgenerational epigenetic inheritance: from phenomena ... · the molecular basis of epigenetic inheritance has become the goal of a growing ﬁeld of research. Identifying the